Soil transmitted helminths remain the most prevalent of all chronic human infections, with an estimated two billion people infected worldwide. Field and experimental studies have shown that immunity in infected individuals is associated with expression of T helper type 2 (TH2) cytokines, while persistent heavy infections can result in overproduction of pro-inflammatory cytokines and the development of severe intestinal inflammation. The long term goals of this proposal are to define the immunological pathways that control T helper cell differentiation and subsequent infection outcome, including intestinal inflammation. Employing experimental Trichuris infection of mice, preliminary studies identified two critical roles for IL-25 (IL-17E) in regulating the immune response following infection: first, IL-25 expression is necessary for the development of protective TH2 responses in resistant mice; second, during persistent infection, IL-25 is an important immunoregulatory cytokine that prevents the development of infection- induced intestinal inflammation. However, the cellular and molecular pathways that orchestrate the effects of IL-25 during Trichuris infection remain unknown. Using cell lineage-specific deletions in transcription factors, cytokines or cytokine receptors, three specific aims of this project will determine (i) how IL-25 promotes TH2 cytokine responses, (ii) how IL-25 limits expression of macrophage-derived pro-inflammatory cytokines and prevents intestinal inflammation, and (iii) how IL-25 regulates the maintenance and function of Trichuris-responsive TH2 memory cells. In addition to testing the prophylactic and therapeutic potential of IL-25 during helminth infection, the findings of these studies will have broader implications for the treatment of multiple TH2 cytokine-associated inflammatory diseases including asthma, allergy and ulcerative colitis. NARRATIVE: An estimated two billion people worldwide are infected with soil transmitted helminth parasites. Although there is strong evidence that T helper type 2 (Th2) cytokines are critical for immunity to infection, the early events that promote protective Th2 cytokine responses are poorly defined. The goals of this proposal are to understand how protective immune responses are initiated and to employ this knowledge in the design of successful new anti-helminth vaccines.